This invention relates to the field of antimicrobials and antivirals for the treatment of infections and compounds that increase longevity.
The growing problem of antibiotic resistant bacteria (see Chambers H. F., Emerg. Infect. Dis. 7:178-182 (2001); Hecht D. W., Clin. Infect. Dis. 39:92-97 (2004); Jacobs M. R., Am. J. Med. 117 Suppl. 3A:3S-15S (2004); Molbak K., Clin. Infect. Dis. 41:1613-1620 (2005); Shah et al., Res. Microbiol. 155:409-421 (2004); Wisplinghoff et al., Clin. Infect. Dis. 39:309-317 (2004); and Zinner S. H., Expert Rev. Anti. Infect. Ther. 3:907-913 (2005)) and the imminent threat of biowarfare agents (see Lane et al., Nat. Med. 7:1271-1273 (2001)) points to a need for new anti-infective therapies. However, the rate of new antimicrobial and antiviral discovery is unlikely to meet the expected need for the foreseeable future (see Boggs et al., Clin. Microbiol. Infect. 10 Suppl. 4:32-36 (2004); Bush K., Clin. Microbiol. Infect. 10 Suppl. 4:10-17 (2004); Dougherty et al., Curr. Pharm. Des. 8:1119-1135 (2002); Schmid M. B., Nat. Rev. Microbiol. 2:739-746 (2004); Silver L. L., IDrugs 8:651-655 (2005); and Walsh C., Nat. Rev. Microbiol. 1:65-70 (2003)). Specific problems include the over-mining of cultivable microorganisms (see Osburne et al., ASM News 66:411-417 (2000)), a high background of toxic compounds or compounds with poor pharmacokinetic properties in synthetic compound libraries (see Projan et al., Clin. Microbiol. Infect. 10 Suppl 4:18-22 (2004); and Lipinski et al., Nature 432:855-861 (2004)), and the inability of most synthetic leads to penetrate across the multi-drug resistance (MDR) barrier of Gram-negative bacteria (see Li et al., Drugs 64:159-204 (2004)). The increased use of in vitro assays for small-molecule discovery that bear little resemblance to the biological systems in which the drugs need to function may also be responsible for the decline in the rate of drug discovery (see Lipinski et al., Nature 432:855-861 (2004); Horrobin D. F., Nat. Rev. Drug Discov. 2:151-154 (2003); Williams M., Curr. Opin. Investig. Drugs 5:29-33 (2004)). Efforts to identify new antifungal compounds have been hindered by the fact that most compounds that have antifungal activity in vitro are also toxic to mammalian cells.
Plant pathogenic diseases are also of concern because they cause damage to plants and plant products. Phytopathogens produce disease in plants by any number of methods including: (1) consuming host cell nutrients; (2) killing or disrupting host cell metabolism through toxins, enzymes, or growth-regulators; (3) affecting photosynthesis by inducing chlorosis (e.g., by degrading chloroplasts); and (4) blocking conductive tissues and interfering with normal physiological processes.
Crop plants, ornamentals, trees, and shrubs are especially vulnerable to diseases caused by bacteria, fungi, and viruses. Phytopathogenic bacteria, for example, cause the development of many disease symptoms including leaf spots and blights, soft-rots, wilts, overgrowths, scabs, and cankers. Bacterial diseases occur most commonly on vegetables (and some ornamentals) that have fleshy storage tissues, such as potatoes, carrots, onions, iris, or hyacinth. They may also occur in plants bearing fleshy fruit (such as cucumber, squash, eggplant, or tomato), as well as in leafy plants (such as cabbage, celery, lettuce, or spinach). Plant bacterial diseases occur throughout the world and cause serious damage to crops in the field, in transit, and in storage.
A facile bioassay compatible with high throughput screening technologies that simultaneously evaluated libraries of chemical compounds for antimicrobial and antiviral activity and host toxicity in the context of a live-animal, or plant seedling, infection model could solve some of the main obstacles in current antimicrobial discovery. There is a need in the art for the development of new antimicrobial and antiviral compounds.